Hepatitis B virus (HBV) is one of the leading causes of morbidity and mortality of human population in all over the world. According to WHO, 2 billion people have been infected with HBV, out of them approximately 3.5 million people are suffering from the chronic HBV infection.1 Due to severe infection of this virus, worldwide annually 0.5-1.2 million deaths are reported. The untreated HBV infection can develop in liver failure, cirrhosis and eventually hepatocellular carcinoma that result in an urgent need for liver transplantation. However, various drugs and vaccines have introduced for the treatment of the HBV infection, but none of them became a successful candidate for complete eradication of this virus.2 A particular class of nucleos(t)ides are accessible for the treatment of HBV infection.3 Theses nucleos(t)ides inhibit viral reverse transcriptase (RT)/DNA polymerase which is an essential enzyme for DNA synthesis in the virus. Based on similar mechanism Lamivudine was first introduced for HBV treatment. After a period of therapy lamivudine-resistant HBV (LVDr) was observed in a significant number of patients.4 Now a day's Entecavir and Tenofovir are most prescribed drugs for HBV treatment.5 A long-term therapy of these drugs promotes double and triples mutation in virus and becomes drug-resistant HBV.6 Recently, reported a triple mutation in the virus (L180M+M204V+S202G) limits the use of entecavir/lamivudine.7 These double and triple mutations in virus have become a major challenge for the treatment of HBV.8 There are no any drugs that can suppress the resistance of virus, and these hurdles restrain treatment of resistant HBV. So it is in high demand for researchers to discover a new molecule that can fight against these mutations and provide a success full treatment for HBV.

Since past two decades in search of new moieties for antiviral agents, our group has involved in the discovery of fluoro-containing nucleoside. To overcome the drug resistant problem of HBV, we invented 2′-fluoro-6′-methylene-carbocyclic adenosine (FMCA) and its monophosphate prodrug (FMCAP, above figure). FMCA has demonstrated a significant activity against wild-type as well as lamivudine, adefovir, and double lamivudine/entecavir-resistant mutants.9 Furthermore, it has tested against lamivudine/entecavir-resistant clone (L180M+M204V+S202G) that has become a core challenge for presently use drugs for the treatment of HBV. Fortunately, FMCA demonstrated potential antiviral activity against wild-type as well as lamivudine/entecavir-resistant. In many cases, it has well observed and reported in the literature that mono-phosphorylation is the rate limiting step for the activity of parental nucleoside.10,11 So the monophosphate prodrug of FMCA was synthesized and surprisingly pro-drug (FMCAP) has demonstrated a 12-fold increase in anti-HBV activity against triple mutant core (L180M+M204V+S202G) of entecavir/lamivudine-resistant.12 The investigations of mitochondrial and cellular toxicity studies of FMCA have also done, and there is no significant toxicity has observed up to 100 μM. By the finding of the above results, it has become a great interest to examine expanded in-vivo activities of FMCA against drug-resistant HBV. Therefore, for further biological screening large quantities of FMCA was required. Consequently, development of a most possible, realistic and cost effect synthesis of FMCA was in urgent need.
However, in our previous communication, we have reported the synthesis of FMCA via Vince lactam in 14 steps.13 But due to the low yield of certain steps limits this process for the large scale synthesis. Furthermore, the lack of commercial availability of carbocyclic sugar 1 was also a prime challenge for the synthesis of these kinds of carbocyclic based nucleos(t)ide. Our group focused on the synthesis of carbocyclic nucleoside from D-ribose and a convenient method has been reposed.14 Many commercial vendors adopted this synthesis and now the supply of carbocyclic ketone 1 is readily available on demand. Therefore, herein we report a highly practical synthesis of FMCA in 7 steps by using carbocyclic sugar 1. The straightforward handling of reactions, enclosing with fewer steps approach and use of cheap reagents makes this synthesis more convenient for scalable synthesis of FMCA. This synthesis may easily be used for the large-scale synthesis of FMCA and its pro-drug FMCAP. During the standardization of this synthesis, an interesting 2′-deoxy-carbocylic sugar 5, and 6 were obtained. It is noteworthy that synthesis of 2-deoxy carbocyclic sugars is very critical. The preparation of 2-deoxy carbocyclic sugars requires robust, expensive synthesis for the construction of this kind of sugar. This process may be used for the synthesis of 2-deoxy sugars. In addition compound 6 is attractive carbocyclic sugar intermediate that can be utilized in the scalable synthesis of entecavir15,16, as well as in the synthesis of other 2′-deoxy-carbocylic nucleos(t)ides. Compound 5 may also serve as the core carbocyclic sugar for the construction of various diversified nucleos(t)ides, those can be tested against a variety of harmful viruses, which are the major threat to humans life.